Design and Characterization of a Pyridone-Containing EZH2 Inhibitor Phosphate Prodrug
| Autor: | Kephart Susan Elizabeth, Manfred Kraus, Hovhannes J. Gukasyan, Sutton Scott Channing, Joseph H Lee, Zehnder Luke Raymond, Shinji Yamazaki, Pei-Pei Kung, Buwen Huang, Connie Fan |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Lymphoma B-Cell Pyridones Cell Antineoplastic Agents 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Mice Pharmacokinetics In vivo Oral administration Cell Line Tumor Drug Discovery medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Prodrugs 030304 developmental biology 0303 health sciences Chemistry EZH2 Prodrug Phosphate Combinatorial chemistry Xenograft Model Antitumor Assays 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Cell culture Drug Design Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 64(3) |
| ISSN: | 1520-4804 |
| Popis: | A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo. |
| Databáze: | OpenAIRE |
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